Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131)

Abstract

Purpose: Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with BRAF mutations outside the V600 locus, and in BRAF fusions. Thus, Subprotocol R of the NCI-MATCH study tested the MEK inhibitor trametinib in this population.

Patients and methods: The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with prespecified fusions and non-V600 mutations in BRAF were assigned to Subprotocol R using the NCI-MATCHBOX algorithm. The primary endpoint was objective response rate (ORR).

Results: Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a BRAF fusion and 31 had BRAF mutations (13 and 19 with class 2 and 3 mutations, respectively). There were no complete responses; 1 patient (3%) had a confirmed partial response (patient with breast ductal adenocarcinoma with BRAF G469E mutation) and 10 patients had stable disease as best response (clinical benefit rate 34%). Median progression-free survival (PFS) was 1.8 months, and median overall survival was 5.7 months. Exploratory subgroup analyses showed that patients with colorectal adenocarcinoma (n = 8) had particularly poor PFS. No new toxicity signals were identified.

Conclusions: Trametinib did not show promising clinical activity in patients with tumors harboring non-V600 BRAF mutations, and the subprotocol did not meet its primary endpoint.

Figure 1:

CONSORT diagram showing numbers of patients assigned, enrolled, and evaluable, as well as reasons for lack of enrollment or evaluability. LVEF: left ventricular ejection fraction; ULN: upper limit of normal.

Figure 2:

(A) Waterfall plot showing depth of response at best change from baseline in target lesion size; best confirmed response noted as PD (progressive disease), SD (stable disease), or PR (partial response) in 24 patients whose best change in target lesion size was evaluable (6 patients without any follow-up imaging assessment and 3 patients without confirmatory follow-up assessment of their target lesions were not included), triangle denotes new lesion as cause of PD; (B) “Swimmer’s” plot showing treatment duration for all 32 evaluable patients and their occurrence of response (*), disease progression (+) and death (#); (C) Progression-free survival (1 patient was censored at registration and did not contribute to the analysis); (D) Overall Survival

Figure 3:

Oncoprint showing spectrum and allele frequency of identified BRAF mutations, co-occurring mutations, histology, and best overall response).